CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

737 CSF TB BACILLARY LOAD PREDICTS 2-WEEK MORTALITY IN HIV- ASSOCIATED TB MENINGITIS

Emily Martyn 1 , Ananta Bangdiwala 2 , Enock Kagimu 1 , Morris K. Rutakingirwa 1 , John Kasibante 1 , Michael Okirwoth 1 , Gavin Stead 1 , Vincent Wadda 3 , Matt Pullen 2 , Tyler Bold 2 , David B. Meya 1 , David R. Boulware 2 , Nathan C. Bahr 4 , Fiona Cresswell 5 1 Infectious Disease Institute, Kampala, Uganda, 2 University of Minnesota, Minneapolis, MN, USA, 3 Mulago National Referral Hospital, Kampala, Uganda, 4 University of Kansas, Lawrence, KS, USA, 5 London School of Hygiene & Tropical Medicine, London, UK Background: Tuberculous meningitis (TBM) carries a ~40% in-hospital mortality in HIV-positive persons and neurologic sequelae are frequent among survivors. WHO has recommended GeneXpert MTB/RIF Ultra (Ultra), a fully automated PCR assay, as the initial TBM diagnostic test. TB bacillary load can be estimated by PCR Cycle threshold (Ct) values, which represent the number of PCR cycles required for probe signal to reach a detection threshold (low Ct value = high bacillary load). Based on PCR Ct values and configuration of probe positivity, Ultra reports 5 semi-quantitative categories of: trace, very low, low, medium and high. We aimed to explore whether CSF TBbacillary load (by Ct value or semi-quant category) is associated with mortality. Methods: We prospectively enrolled 107 HIV+ Ugandans with TBM from April 2015 to August 2019. Ultra semi-quant category and Ct tertiles were separately analysed as predictors of 2-week mortality. We investigated associations between Ct and baseline clinical and CSF parameters. Results: Subjects in the lowest Ct tertile (i.e. highest bacillary load) had 60% 2-week mortality; significantly worse than the intermediate (18%) and highest (26%) Ct tertiles and Ultra-negative (31%) probable TBM cases (Figure, p=0.03). Using the reported Ultra semi-quant category, subjects with medium-low semi-quant category also trended toward worse 2-week survival (50%) compared to very low (27%), trace (27%) and negative (31%) categories but was not statistically significant (p=0.25). Participants with negative Ultra results (probable TBM) had evidence of CSF inflammation and a high mortality (31%), suggesting a bacillary load undetectable by Ultra is not associated with improved survival. TB bacillary load was not associated with focal neurological deficit but a high bacillary load was associated with higher CSF lactate levels (p=0.04). Conclusion: High CSF TB bacillary load, as measured by Ultra Ct, is associated with over 2-fold higher 2-week mortality in HIV-associated TBM, being a better predictor than the reported Ultra semi-quant category. This is the first study to investigate Ultra Ct values and TBM outcomes and raises the possibility of Ultra Ct values being used to identify patients at greatest risk of death and who may benefit from enhanced supportive care or intensified TBM treatment.

736 DRUG-RESISTANCE MUTATIONS AND TUBERCULOSIS MORTALITY IN HIGH-BURDEN COUNTRIES Veronika Skrivankova 1 , Matthias Egger 2 , for the IeDEA TB Genomics Group 1 Institute of Social and Preventive Medicine, Bern, Switzerland, 2 University of Bern, Bern, Switzerland Background: Strategies to control Mycobacterium tuberculosis (Mtb) drug resistance include universal access to quality-controlled drug resistance (DR) testing coupled with aligned treatment regimens and patient centred treatment support. We examined the impact of drug resistance mutations (DRM) on mortality in HIV+ and HIV- patients with TB in eight high-burden countries. Methods: We included 247 HIV+ and 335 HIV- adult patients diagnosed with TB in Kenya, South Africa, Democratic Republic of the Congo, Nigeria, Côte d’Ivoire, Peru and Thailand; 60 patients died during treatment. Sampling was stratified by HIV status and on-site DR diagnosis, as determined by locally available tests (Xpert/LPA and/or culture). Whole genome sequences (WGS) were scanned for high-confidence DRM. We compared the DR profiles diagnosed at sites with the DRM fromWGS to identify the most common mutations and the DR missed locally. We used logistic regression to examine their association with mortality during TB treatment, adjusted for sex, age and HIV status. We ran a separate model for each DRM with frequency >20 and for combined groups of rare DRM. The reference group consisted of TB patients with pan-susceptible Mtb based on WGS. Results: The most common mutations in our sample were S315T, S450L, L79S, C-15T, M306V, D435V, M306I and K43R (details in Table 1). While DR to rifampicin (RIF) was missed only in 2% of cases, DR to isoniazid (INH) was missed in 25% of cases and for all other drugs in >70% cases. The DRM individually associated with the largest increase in mortality were S315T with OR 3.7 (95%CI: 2.2-6.5), D453V with OR 3.8 (95%CI: 1.7-8.4) and L79S with OR 4.13 (95%CI: 2-8.5). The OR for groups of rare DRM conferring resistance to RIF, ethambutol (EMB) and all second-line drugs were also statistically significant, ranging from 2.9 to 4.5. Results were similar in HIV+ and HIV- patients. Conclusion: We identified several DRM associated with increased mortality in TB patients from eight high-burden countries. Many of the conferred DR were missed by local DR tests, potentially leading to an inadequate treatment. Our results highlight the critical need of rapid molecular point-of-care DR tests that cover a broader range of DRM and thus could contribute to more effective treatment and reduced mortality among patients with MDR TB.

Poster Abstracts

738 MORTALITY IN ADULT HIV/MDR-TB BY ART USE: INDIVIDUAL PATIENT DATA META-ANALYSIS Gregory P. Bisson 1 , Mayara Bastos 2 , Jonathon Campbell 2 , Didi Bang 3 , James C. Brust 4 , Petros Isaakidis 5 , Christoph Lange 6 , Giovanni Battista Migliori 7 , Jean

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